Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
  • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
  • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Definitions

• the present invention relates to a method for preparation of erythromycin derivatives.
• the compound represented by Formula (II): (wherein R 1 represents a hydrogen atom or a lower alkyl group, and R 2 represents a lower alkyl group) is described in, for example, JP 6-56873 A and JP 9-100291 A . These compounds are known to have the ability to enhance movement of the digestive tract.
• JP 9-100291 A teaches an improved method for preparing the compound of the present invention, represented by Formula (II): (wherein R 1 represents a hydrogen atom or a lower alkyl group, and R 2 represents a lower alkyl group), which overcomes the above problems associated with the preparation methods found in JP 6-56873 A and Bioorg. & Med. Chem. Lett., vol. 4(11), 1347 (1994 ).
• This publication discloses a method in which a compound corresponding to Compound 5 of the present invention is carbamated in the presence of toluene to prepare a compound corresponding to Compound 6 of the present invention. It also discloses a method in which a compound corresponding to Compound 6 of the present invention is catalytically hydrogenated under a hydrogen atmosphere using a palladium-carbon catalyst to prepare a compound corresponding to Compound 7 of the present invention. Further, it discloses a method in which a compound corresponding to Compound 8 of the present invention is dissolved in methanol together with fumarate and then crystallized by addition of isopropanol to prepare crystals of a fumarate salt of Compound 8 according to the present invention.
• the present invention was made in view of the problems stated above and aims to provide an efficient method for preparing erythromycin derivatives. It also aims to provide a method for preparing erythromycin derivatives of high quality.
• the inventors of the present invention found an efficient method for preparing erythromycin derivatives and completed one aspect of the present invention. Also, the inventors of the present invention found a method for preparing erythromycin derivatives of high quality and completed another aspect of the present invention.
• the present invention relates to a method for preparing a fumarate salt of a compound represented by Formula (II): (wherein R 1 represents a hydrogen atom or a lower alkyl group, and R 2 represents a lower alkyl group), which comprises:
• the present invention also relates to a method for preparing a fumarate salt of a compound represented by Formula (II): (wherein R 1 represents a hydrogen atom or a lower alkyl group, and R 2 represents a lower alkyl group), which comprises:
• the present invention relates to a method for preparing a crystal of a fumarate salt of a compound represented by Formula (II): (wherein R 1 represents a hydrogen atom or a lower alkyl group, and R 2 represents a lower alkyl group), which comprises:
• the present invention relates to a method for preparing a crystal of a fumarate salt of a compound represented by Formula (II): (wherein R 1 represents a hydrogen atom or a lower alkyl group, and R 2 represents a lower alkyl group), which comprises:
• the present invention relates to a method for preparing a crystal of a fumarate salt of a compound represented by Formula (II): (wherein R 1 represents a hydrogen atom or a lower alkyl group, and R 2 represents a lower alkyl group), which comprises:
• the present invention also relates to a method for preparing a crystal of a fumarate salt of a compound represented by Formula (II): (wherein R 1 represents a hydrogen atom or a lower alkyl group, and R 2 represents a lower alkyl group), which comprises:
• the present invention also relates to a method for preparing a compound represented by Formula (III): (wherein R 1 represents a hydrogen atom or a lower alkyl group, R 3 represents a carbamate group, and R 4 represents a hydrogen atom or a carbamate group), which comprises carbamating a compound represented by Formula (I): (wherein R 1 represents a hydrogen atom or a lower alkyl group) in the presence of a cyclic ether or a carboxylic ester.
• the present invention relates to a method for preparing a compound represented by Formula (IV): (wherein R 1 represents a hydrogen atom or a lower alkyl group), which comprises removing all carbamate groups from a compound represented by Formula (III): (wherein R 1 represents a hydrogen atom or a lower alkyl group, R 3 represents a carbamate group, and R 4 represents a hydrogen atom or a carbamate group) in the presence of sodium bicarbonate.
• the present invention also relates to a method for preparing a crystal of a fumarate salt of a compound represented by Formula (II): (wherein R 1 represents a hydrogen atom or a lower alkyl group, and R 2 represents a lower alkyl group), which comprises crystallizing a fumarate salt of the compound represented by Formula (II) from isopropanol.
• the present invention relates to a method for preparing a crystal of a fumarate salt of a compound represented by Formula (II): (wherein R 1 represents a hydrogen atom or a lower alkyl group, and R 2 represents a lower alkyl group), which comprises recrystallizing a crystal of a fumarate salt of the compound represented by Formula (II) from isopropanol.
• the present invention relates to a method for preparing a crystal of a fumarate salt of a compound represented by Formula (II): (wherein R 1 represents a hydrogen atom or a lower alkyl group, and R 2 represents a lower alkyl group), which comprises recrystallizing a crystal of a fumarate salt of the compound represented by Formula (II) from isopropanol and then from a mixed methanol/isopropanol solvent.
• R 1 represents a hydrogen atom or a lower alkyl group
• R 2 represents a lower alkyl group
• the present invention relates to a method for preparing a crystal of a fumarate salt of a compound represented by Formula (II): (wherein R 1 represents a hydrogen atom or a lower alkyl group, and R 2 represents a lower alkyl group), which comprises crystallizing a fumarate salt of the compound represented by Formula (II) from isopropanol to give a crystal of the fumarate salt of the compound, and recrystallizing the crystal from isopropanol and then from a mixed methanol/isopropanol solvent.
• R 1 represents a hydrogen atom or a lower alkyl group
• R 2 represents a lower alkyl group
• a lower alkyl group refers to a linear or branched C 1 -C 6 alkyl group, including a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, a pentyl group and a hexyl group.
• the lower alkyl group in R 1 is preferably a methyl group, an ethyl group, an n-propyl group or an isopropyl group, and particularly preferably a methyl group.
• the lower alkyl group in R 2 is preferably a methyl group, an ethyl group, an n-propyl group or an isopropyl group, and particularly preferably an isopropyl group.
• a chloroformate refers to an alkyl chlorocarbonate, including methyloxycarbonyl chloride, ethyloxycarbonyl chloride, 2-phenylethyloxycarbonyl chloride, tert-butyloxycarbonyl chloride, vinyloxycarbonyl chloride, allyloxycarbonyl chloride, p-methoxybenzyloxycarbonyl chloride, p-nitrobenzyloxycarbonyl chloride and benzyloxycarbonyl chloride.
• a carbamate group refers to an alkyl carbonate group, including a methyloxycarbonyl group, an ethyloxycarbonyl group, a 2-phenylethyloxycarbonyl group, a tert-butyloxycarbonyl group, a vinyloxycarbonyl group, an allyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group and a benzyloxycarbonyl group.
• the carbamate group in R 3 and R 4 is preferably a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group or an allyloxycarbonyl group, and particularly preferably a benzyloxycarbonyl group.
• alcohols examples include methanol, ethanol, n-propanol, i-propanol, n-butanol, sec-butanol, t-butanol, pentanol, hexanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, ethylene glycol, 1,3-propanediol, 1,4-butanediol and 1,5-pentanediol.
• An alcohol-containing solvent refers to a solvent comprising one or more alcohols. Examples include isopropanol and a mixed methanol/isopropanol solvent.
• One-pot means that in a series of reactions, each reaction product is provided for the next reaction without isolation and purification.
• the one-pot reaction defined here encompasses not only a series of reactions conducted in a single reaction vessel, but also a series of reactions conducted in a plurality of reaction vessels (e.g., by transferring the reaction mixture from one vessel to other) without isolation and purification.
• the one-pot reaction is conducted in a single reaction vessel.
• -fold amount relative to a material is intended to mean a weight-to-weight ratio relative to the material.
• 2-fold amount relative to a material means a 2:1 weight-to-weight ratio relative to the material.
• "-fold amount” relative to a material is intended to mean a volume-to-weight ratio of the fluid to the material.
• 2-fold amount of a solvent relative to a material means a 2:1 volume-to-weight ratio of the solvent (e.g., 2 liter) to the material (e.g., 1 kg).
• the preparation method of the present invention comprises a first step of carbamating a compound represented by Formula (I) to give a compound represented by Formula (III), a second step of removing all carbamate groups from the compound represented by Formula (III) to give a compound represented by Formula (IV), a third step of alkylating the nitrogen atom at the 3'-position of the compound represented by Formula (IV) to give a compound represented by Formula (II), a fourth step of converting the compound represented by Formula (II) into a fumarate salt to give a fumarate salt of the compound represented by Formula (II), and a fifth step of recrystallizing the fumarate salt of the compound represented by Formula (II) to give a purified crystal of the fumarate salt of the compound represented by Formula (II).
• the preparation method of the present invention comprises the first, second, third and fourth steps mentioned above. In another embodiment, the preparation method of the present invention comprises the first, second and third steps mentioned above. In another embodiment, the preparation method of the present invention comprises the first step mentioned above. In another embodiment, the preparation method of the present invention comprises the second step mentioned above. In another embodiment, the preparation method of the present invention comprises the fourth step mentioned above. In a final embodiment, the preparation method of the present invention comprises the fifth step mentioned above.
• these first and second steps are preferably conducted in one-pot.
• these second and third steps are preferably conducted in one-pot.
• these third and fourth steps are preferably conducted in one-pot.
• these fourth and fifth steps are preferably conducted in one-pot.
• Compound 1 as a compound represented by Formula (I) is reacted with a chloroformate under basic conditions to give Compound 2 as a compound represented by Formula (III) (first step).
• the chloroformate used in carbamation is preferably benzyloxycarbonyl chloride, p-methoxybenzyloxycarbonyl chloride or allyloxycarbonyl chloride, and particularly preferably benzyloxycarbonyl chloride.
• Examples of a base available for use include inorganic bases such as sodium bicarbonate, potassium carbonate and sodium hydroxide, and tertiary amines such as triethylamine and diisopropylethylamine.
• inorganic bases more preferred are sodium bicarbonate and potassium carbonate, and particularly preferred is sodium bicarbonate.
• Any solvent may be used as long as it does not affect the reaction, including aromatic hydrocarbon solvents, carboxylic esters and ethers. Preferred are carboxylic esters and ethers, and more preferred are carboxylic esters. A preferred aromatic hydrocarbon solvent is toluene. Examples of carboxylic esters include ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate and ethyl propionate, with acetic esters being preferred and with ethyl acetate being more preferred.
• Preferred ethers are cyclic ethers.
• cyclic ethers examples include oxirane, tetrahydrofuran, tetrahydropyran and dioxane, with tetrahydrofuran being preferred.
• the solvent used for carbamation is preferably toluene, tetrahydrofuran or ethyl acetate, more preferably tetrahydrofuran or ethyl acetate, and particularly preferably ethyl acetate.
• the reaction temperature usually ranges from about 0°C to 120°C, preferably 20°C to 110°C, more preferably 40°C to 80°C, particularly preferably 45°C to 70°C.
• the reaction time usually ranges from about 0.5 to 12 hours, preferably 0.5 to 10 hours, more preferably 0.5 to 3 hours.
• the chloroformate is generally used in an amount of 5 to 15 equivalents, preferably 7 to 13 equivalents, more preferably 8 to 12 equivalents, particularly preferably 10 to 12 equivalents, relative to the compound represented by Formula (I).
• the base is generally used in an amount of 5 to 18 equivalents, preferably 7 to 15 equivalents, more preferably 9 to 12 equivalents, relative to the compound represented by Formula (I).
• All carbamate groups are removed from Compound 2 as a compound represented by Formula (III) to give Compound 3 as a compound represented by Formula (IV) (second step). Removal of carbamate groups is accomplished by a standard deprotection reaction. Examples of such a deprotection reaction include catalytic hydrogenation and acid treatment. Preferred are catalytic hydrogenation in the presence of a palladium-carbon catalyst, treatment with an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid or fumaric acid, and treatment with an inorganic acid such as hydrochloric acid or phosphoric acid. Particularly preferred is catalytic hydrogenation in the presence of a palladium-carbon catalyst.
• a palladium-carbon catalyst is used in the deprotection reaction
• this catalyst is generally used in a 0.01- to 1.0-fold amount, preferably in a 0.1- to 0.5-fold amount, more preferably in a 0.13- to 0.39-fold amount, relative to the compound represented by Formula (I) used in the first step.
• Catalytic hydrogenation is preferably performed under basic conditions.
• Examples of a base available for this purpose include inorganic bases such as sodium bicarbonate, potassium carbonate and sodium hydroxide, and tertiary amines such as triethylamine and diisopropylethylamine.
• Preferred are inorganic bases, more preferred are sodium bicarbonate and potassium carbonate, and particularly preferred is sodium bicarbonate.
• hydrogen As a hydrogen source, hydrogen, ammonium formate or the like may be used.
• catalytic hydrogenation may be performed under pressure, preferably at a pressure of about 0.01 to 1.0 MPa, more preferably 0.05 to 0.5 MPa.
• Any solvent may be used as long as it is inert to the reaction, preferably including alcohol solvents and ester solvents. More preferred are methanol, ethanol and ethyl acetate, and particularly preferred is methanol.
• the reaction temperature usually ranges from about 0°C to 60°C, preferably 10°C to 50°C, more preferably 20°C to 40°C.
• the reaction time usually ranges from about 0.5 to 3 hours, preferably 1 to 2 hours.
• the nitrogen atom at the 3'-position of the desosamine ring in Compound 3 as a compound represented by Formula (IV) is alkylated to give Compound 4 as a compound represented by Formula (II) (third step).
• Examples of an alkylating agent used for alkylation in the third step include alkyl halides, alkyl tosylates and alkyl mesylates, with alkyl halides being preferred.
• a preferred alkyl halide has an isopropyl group as its alkyl moiety.
• Examples of an isopropylating agent include isopropyl iodide, isopropyl methanesulfonate and isopropyl p-toluenesulfonate, with isopropyl iodide being preferred.
• Examples of a base available for use include organic bases (e.g., amines) and inorganic bases. Preferred are diisopropylethylamine, triethylamine, morpholine, piperidine, pyrrolidine and pyridine, and more preferred is triethylamine. Any solvent may be used as long as it is inert to the reaction.
• aprotic polar solvents and alcohol solvents Preferred are aprotic polar solvents and alcohol solvents, and more preferred are dimethylimidazolidinone, dimethylformamide, acetonitrile and the like.
• the alkylating agent is generally used in an amount of 6 to 15 equivalents, preferably 7 to 13 equivalents, more preferably 8 to 12 equivalents, particularly preferably 8 to 10 equivalents, relative to the compound represented by Formula (I) used in the first step.
• the base is generally used in an amount of 5 to 15 equivalents, preferably 7 to 13 equivalents, more preferably 8 to 12 equivalents, relative to the compound represented by Formula (I).
• the solvent is generally used in a 2- to 12-fold amount, preferably in a 3- to 10-fold amount, more preferably in a 3- to 8-fold amount, particularly preferably in a 3- to 6-fold amount, relative to the compound represented by Formula (I) used in the first step.
• the reaction temperature usually ranges from about 0°C to 130°C, preferably 50°C to 100°C, more preferably 60°C to 90°C.
• the reaction time usually ranges from about 3 hours to 10 days, preferably 5 to 10 hours.
• Compound 4 as a compound represented by Formula (II) is converted into a fumarate salt to give a fumarate salt of Compound 4 as a fumarate salt of the compound represented by Formula (II) (fourth step).
• Conversion into a fumarate salt is accomplished by a standard technique for salt formation.
• a solvent available for use include alcohol solvents, ether solvents, acetone and ethyl acetate, with alcohol solvents being preferred.
• alcohol solvents being preferred.
• preferred are methanol, ethanol and isopropanol, more preferred are methanol and isopropanol, and particularly preferred is isopropanol.
• solvents may be used alone or in combination.
• fumaric acid is generally used in an amount of 0.3 to 2 equivalents, preferably 0.3 to 1 equivalent, more preferably 0.4 to 0.8 equivalents, particularly preferably 0.4 to 0.6 equivalents, relative to the compound represented by Formula (II).
• the reaction temperature usually ranges from about 20°C to 100°C, preferably 0°C to 90°C, more preferably 20°C to 80°C.
• the reaction time usually ranges from about 1 to 6 hours, preferably 3 to 4 hours.
• the fumarate salt of Compound 4 as a fumarate salt of the compound represented by Formula (II) is purified to give a purified fumarate salt of Compound 4 (fifth step).
• a fumarate salt of the compound represented by Formula (II) is purified, as needed. Purification is preferably accomplished by recrystallization.
• a solvent for recrystallization include ester solvents which may contain water, alcohol solvents which may contain water, ether solvents which may contain water, and mixed solvents thereof.
• Preferred are isopropanol, a mixed methanol/isopropanol solvent and a mixed ethyl acetate/water solvent, and more preferred are isopropanol and a mixed methanol/isopropanol solvent.
• the mixing ratio between methanol and isopropanol preferably ranges from 10:90 to 50:50, more preferably 20:80 to 30:70.
• the mixing ratio between ethyl acetate and water preferably ranges from 99.5:0.5 to 95:5, more preferably 99:1 to 96:4, particularly preferably 98.5:1.5 to 97:3.
• the above recrystallization step is performed at decreasing temperature. It usually starts at a temperature of 10°C to 100°C, preferably 10°C to 90°C, more preferably 20°C to 80°C, particularly preferably 70°C to 80°C.
• the temperature usually decreases at a rate of 5°C/hour to 130°C/hour, preferably 10°C/hour to 120°C/hour, more preferably 10°C/hour to 50°C/hour, particularly preferably 10°C/hour to 30°C/hour.
• the temperature usually decreases to a final temperature of -10°C to 0°C.
• the fumarate salt is preferably recrystallized from isopropanol and then from a mixed methanol/isopropanol solvent.
• Example 1 The compound prepared in Example 1 was used without isolation and purification. To this compound, methanol (88.5 kg), 10% palladium-carbon (3.6 kg) and sodium bicarbonate (16.2 kg) were added and stirred under a hydrogen atmosphere (0.1 to 0.4 MPa) for 1 hour at 25°C to 50°C. As a result, the starting Z compound (Compound 6) and its reaction intermediate (Compound 6 lacking one benzyloxycarbonyl group by deprotection) completely disappeared and they were each converted into the titled compound. After the palladium-carbon was filtered off, the filtrate was concentrated under reduced pressure.
• Example 2 The compound prepared in Example 2 was used without isolation and purification. To this compound, 1,3-dimethyl-2-imidazolidinone (58.9 kg) was added. To this solution, triethylamine (19.5 kg) and isopropyl iodide (29.4 kg) were added at 75°C and stirred with heating for 6 hours to convert 98% of the starting monomethyl compound (Compound 7) into the titled compound. After cooling to 30°C or below, ethyl acetate (82.0 kg) and'25% aqueous ammonia (3.6 kg) were added. To this solution, water (70.0 kg) was further added and stirred, followed by partition to remove the aqueous phase. This procedure, where water was added and stirred, followed by partition to remove the aqueous phase, was repeated twice more. The resulting organic phase was concentrated under reduced pressure to give the titled compound.
• 1,3-dimethyl-2-imidazolidinone 58.9 kg
• Example 3 The compound prepared in Example 3 was used without isolation and purification. To this compound, fumaric acid (1.1 kg) and isopropanol (109.9 kg) were added and heated to 71°C, followed by cooling to 10°C or below at a rate of 20°C/hour. The precipitated crystals were collected by filtration to give crystals of the titled compound (wet powders; calculated dry yield: 86.2%; purity: 92.21%). To the wet powders, isopropanol (106.0 kg) was added and heated to 71°C, followed by cooling to 10°C or below at a rate of 20°C/hour. The precipitated crystals were collected by filtration to give crystals of the titled compound (wet powders; purity: 98.74%).
• the crystals prepared in Example 4 were used without drying. To the crystals, methanol (2.5 volumes per calculated dry weight of the compound prepared in Example 4) and isopropanol (7.5 volumes per calculated dry weight of the compound prepared in Example 4) were added and heated to 60°C, followed by cooling to 0°C or below at a rate of 20°C/hour. The precipitated crystals were collected by filtration to give crystals (wet powders) of the titled compound. The above procedure was repeated once again without drying the resulting crystals to give crystals of the titled compound (wet powders; purity: 99.44%).
• Example 6 The compound prepared in Example 6 was used without isolation and purification. To this compound (20.4 g, 28.6 mmol), methanol (102 mL), 10% palladium-carbon (5.3 g) and sodium bicarbonate (24.0 g, 285.7 mmol) were added and stirred under a hydrogen atmosphere (0.1 to 0.4 MPa) for 1 hour at 25°C to 50°C. As a result, the starting Z compound (Compound 10) and its reaction intermediate (Compound 10 lacking one benzyloxycarbonyl group by deprotection) completely disappeared and they were each converted into the titled compound. After the palladium-carbon was filtered off, the filtrate was concentrated under reduced pressure.
• methanol 102 mL
• 10% palladium-carbon 5.3 g
• sodium bicarbonate 24.0 g, 285.7 mmol
• Example 7 The compound (21.6 g, 30.8 mmol) prepared in Example 7 was used without isolation and purification. To this compound, 1,3-dimethyl-2-imidazolidinone (86 mL) was added. To this solution, triethylamine (31.1 g, 307.5 mmol) and isopropyl iodide (47.0 g, 276.8 mmol) were added at 75°C and stirred with heating for 6 hours to convert 98% of the starting monomethyl compound (Compound 11) into the titled compound. After cooling to 30°C or below, ethyl acetate (500 mL) and 25% aqueous ammonia (5.4 mL) were added.
• Example 8 The compound prepared in Example 8 was used without isolation and purification. To this compound (17.0 g, 22.9 mmol), fumaric acid (1.3 g) and isopropanol (170 mL) were added and heated to 71°C, followed by cooling to 10°C or below at a rate of 20°C/hour. The precipitated crystals were collected by filtration to give crystals (6.8 g) of amo compound (fumarate salt of Compound 12).
• Example 9 The crystals prepared in Example 9 were used without drying. To the crystals (6.59 g), methanol (8.2 mL) and isopropanol (24.8 mL) were added and heated to 60°C, followed by cooling to 0°C or below at a rate of 20°C/hour. The precipitated crystals were collected by filtration to give crystals (4.83 g; purity: 98.77%) of amo compound (fumarate salt of Compound 12).
• the preparation method of the present invention is industrially advantageous in (1) providing improved reaction efficiency and reduced reaction time, (2) allowing dramatic simplification of the process and saving the time and labor required for the process due to elimination of procedures such as solvent replacement, (3) reducing the risk of product decomposition during reaction, (4) reducing the content of residual solvent because the resulting reaction product is easy to dry, (5) yielding compounds of high quality and high purity, etc.
• the preparation method of the present invention is useful for industrial preparation.

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